Abnormal increase in blood uric acid level, i.e., hyperuricemia is a disorder that has close relation to gout, renal dysfunction, urolithiasis, etc. (Diagnosis and Treatment, 2002, 90(2), 244-248; Diagnosis and Treatment, 2002, 90(2), 220-224). It is known that, in organ transplantation (Ren. Fail. 2002 May; 24(3):361-7) or chemotherapy for cancer (Am. J. Health Syst. Pharm. 2003 Nov. 1; 60(21):2213-22), serum uric acid level extremely increases, thereby causing renal dysfunction (tumor lysis syndrome). An agent for treating hyperuricemia may be roughly classified into an uricosuric agent and an uric acid synthesis inhibitor. The uricosuric agent may be ineffective for cases whose renal function has lowered, and therefore allopurinol (Nippon Rinsho, 1996 December; 54(12): 3364-8, and Nippon Rinsho, 2003; 61, Suppl. 1: 197-20), an uric acid synthesis inhibitor, is suitably used for patients having a lowered renal function (Guideline for Treatment for Hyperuricemia, Gout; Treatment Guideline by the Gout/Nucleic Acid Metabolism Society of Japan, 2002). Xanthine oxidase is an enzyme that controls the biosynthesis of uric acid, and a xanthine oxidase inhibitor to inhibit this enzyme is effective for treatment of hyperuricemia and various diseases caused thereby, as an uric acid synthesis inhibitor. Allopurinol is only one xanthine oxidase inhibitor that has been put into practical use at present for clinical treatment.
On the other hand, it is known that xanthine oxidase plays a role as an active oxygen producing enzyme (Drug Metab. Rev. 2004 May; 36(2): 363-75). Active oxygen is a precipitating factor for pathology, as damaging DNA and cells and as inducing inflammatory cytokine production (Free Radic. Biol. Med. 2001 May 15; 30(10): 1055-66). For example, it is known that active oxygen is concerned deeply with autoimmune inflammatory diseases such as ulcerative colitis and Crohn's disease (Scand. J. Gastroenterol. 2001 December; 36(12): 1289-94), and ischemic reperfusion disorder (Biochem. Biophys. Res. Commun. 2004 Mar. 5; 315(2): 455-62). Further, recently, it has been suggested that active oxygen may participate in diabetic nephropathy (Curr. Med. Res. Opin. 2004 March; 20(3): 369-79), cardiac failure (J. Physiol. 2004 Mar. 16; 555 (Pt 3): 589-606, Epub 2003 Dec. 23), cerebrovascular disorder (Stroke, 1989 April; 20(4): 488-94), etc., as one precipitating factor for them. It is known that, in diabetic retinopathy, the increase in the vascular endothelial growth factor (VEGF) level in a vitreous body is deeply concerned with pathologic deterioration, and during the disease, there occurs VEGF expression increase via oxidation stress (Curr. Drug Targets, 2005 June; 6(4): 511-24). A xanthine oxidase inhibitor inhibits the production of active oxygen, and this is therefore effective for treatment for these diseases. In fact, it is reported that allopurinol is effective for human ulcerative colitis (Aliment. Pharmacol. Ther. 2000 September; 14(9): 1159-62), diabetes-accompanied vascular disorder (Hypertension, 2000 March; 35(3): 746-51) and chronic cardiac failure (Circulation, 2002 Jul. 9; 106(2): 221-6).
Thus, the effectiveness of allopurinol, a xanthine oxidase inhibitor, for various diseases is reported, but on the other hand, its serious adverse side effects such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatopathy and renal dysfunction are also reported (Nippon Rinsho, 2003; 61, Suppl. 1: 197-201). It is pointed that one cause of it is that allopurinol has a nucleic acid-analogous structure and inhibits a pyrimidine metabolic pathway (Life Sci. 2000 Apr. 14; 66(21): 2051-70). Accordingly, development of a non-nucleic acid structure xanthine oxidase inhibitor having higher safety and having potent medicinal efficacy is earnestly desired.
Hithertofore, compounds having a xanthine oxidase inhibitory activity are known. For example, 2-phenylthiazole derivatives of the following general formula are reported (Patent Reference 1):
Ar represents
etc.(wherein R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a C1-4 alkyl group, a C1-4 haloalkyl group, OR, S(O)nR, or NRR′ [wherein R and R′ each independently represent a hydrogen atom, an alkyl group, an aryl group or the like; or R and R′, taken together with the nitrogen atom to which they bond, are atoms to form an unsubstituted or substituted, 5- to 7-membered heterocycle] or the like; X represents a hydrogen atom, a C1-4 alkyl group, a carboxyl group or the like; Y represents a hydrogen atom, a C1-4 alkyl group or the like; for their details, the patent publication is referred to).
In addition, as other compounds having a xanthine oxidase inhibitory activity, for example, reported are biarylcarboxylic acid derivatives consisting of two aromatic rings, such as 2-phenylthiazole derivatives (Patent Reference 2 and Patent Reference 3); 3-phenylisothiazole derivatives (Patent Reference 4 and Patent Reference 5); phenylpyrazole derivatives (Patent References 6 to 8 and Non-Patent Reference 1); 2-phenyloxazole derivatives (Patent Reference 9); 2-phenylimidazole derivatives (Patent Reference 9); 2-phenylpyridine derivatives (Patent Reference 10); 2-phenylthiophene derivatives (Patent Reference 11).
The above patent publications do not disclose compounds having a structure of three aromatic rings directly bonding to each other.
On the other hand, compounds of the following general formula (III) are described, having an uricosuric effect and useful for treatment for hyperuricemia (Patent Reference 12):
(wherein A represents an oxygen atom, a sulfur atom or a vinylene group; B represents an oxygen atom, a nitrogen atom, —(CH2)n— [wherein n indicates 0 or 1] or the like; R1 represents a hydrogen atom, a lower alkyl group or the like; R2 represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group or the like; R3 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a lower aminoalkoxy group; R4 represents a nitro group, a cyano group, a halogen atom, a trifluoromethyl group, a tetrazole group, an oxadiazolone group or the like; for their details, the patent publication is referred to).
The patent publication does not concretely disclose triarylcarboxylic acid derivatives.
In addition, as compounds having a triarylcarboxylic acid structure, reported are biphenylpyridine-carboxylic acid derivatives having an antimicrobial effect (Non-Patent Reference 2); biphenylylpyrazole-carboxylic acid derivatives having an antimicrobial effect (Non-Patent Reference 3); biphenylylisothiazole-carboxylic acid derivatives having a nematocidal effect (Patent Reference 13).
However, any of Patent Reference 13 and Non-Patent References 2 and 3 does neither disclose nor suggest a xanthine oxidase inhibiting action and an uric acid synthesis inhibiting action.
Patent Reference 1: WO 92/09279
Patent Reference 2: JP-A-2002-105067
Patent Reference 3: WO 96/31211
Patent Reference 4: JP-A-57-85379
Patent Reference 5: JP-A-6-211815
Patent Reference 6: JP-A-59-95272
Patent Reference 7: WO 98/18765
Patent Reference 8: JP-A-10-310578
Patent Reference 9: JP-A-6-65210
Patent Reference 10: WO 2006/022374
Patent Reference 11: WO 2006/022375
Patent Reference 12: JP-A-2000-1431
Patent Reference 13: U.S. Pat. No. 4,539,328
Non-Patent Reference 1: Bioorganic Medicinal Chemistry Letters, 2001, Vol. 11, pp. 879-882
Non-Patent Reference 2: Pharmazie, 1999, Vol. 54, pp. 178-183
Non-Patent Reference 3: Bioorganic Medicinal Chemistry Letters, 2003, Vol. 13, pp. 2231-2234